A ligand for the aryl hydrocarbon receptor isolated from lung

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-inducible transcription factor that is best known because it mediates the actions of polycyclic and halogenated aromatic hydrocarbon environmental toxicants such as 3-methylcholanthrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin. We report here the successful identification of an endogenous ligand for this receptor; Ϸ20 g was isolated in pure form from 35 kg of porcine lung. Its structure was deduced as 2-(1H-indole-3-carbonyl)-thiazole-4-carboxylic acid methyl ester from extensive physical measurements and quantum mechanical calculations. In a reporter gene assay, this ligand activates the AHR with a potency five times greater than that of ␤-naphthoflavone, a prototypical synthetic AHR ligand. 2-(1H-indole-3-carbonyl)-thiazole-4-carboxylic acid methyl ester competes with 2,3,7,8-[ 3 H]tetrachlorodibenzo-p-dioxin for binding to human, murine, and fish AHRs, thus showing that AHR activation is caused by direct receptor binding, and that recognition of this endogenous ligand is conserved from early vertebrates (fish) to humans.

Protein Expression of Aryl Hydrocarbon Receptors in Human Placentas from Mild Preeclamptic and Early Pregnancies

“…In conclusion, together with the recent findings of endogenous AhR ligands produced by human and animals [ [17], [18]], the current data strongly support the notion that AhR plays important physiological roles in mediating normal differentiation and development of cytotrophoblast as well as placental endothelial cells to maintain successful pregnancy.…”

“…It is possible that AhR might dynamically mediate syncytiotrophoblast differentiation and placental hormonal synthesis, particularly during late pregnancy, to support pregnancy and embryo/fetal development in uteri as AhR null female mice have difficulties to do so [ [6], [7]]. In addition, higher AhR protein levels in term placentas than early pregnant placentas also suggest that the former might be more sensitive to AhR ligands' stimulation regardless if these ligands are derived from exogenous or endogenous sources [ [17], [18]]. …”

The Aryl Hydrocarbon Receptor Ligand ITE Inhibits TGFβ1-Induced Human Myofibroblast Differentiation

“…ITE did reduce the amount of AlamarBlue fluorescence generated in TGF␤1-treated cultures, but this result is not surprising in light of our overall findings of ITE-induced inhibition of TGF␤1-mediated effects. Although ITE is best known as an AhR agonist, 22,27 we ultimately came to the conclusion that the antifibrotic activity of this compound is independent of AhR expression ( Figure 4). We then sought to identify the point in the TGF␤1 signaling pathway targeted by ITE.…”

“…ITE, for example, was initially isolated from porcine lung. 27 Thus, it is unlikely that it exerts toxicity, at least not in the lung at the concentrations at which it is found naturally. Furthermore, given its pulmonary origin and the results of this study, it is tempting to speculate that ITE may serve some natural function in the prevention of pulmonary fibrosis.…”

“…23,25 Candidate endogenous ligands of the AhR include ketocholesterol, bilirubin, indigo, lipoxin A 4 , and tryptophan derivatives such as ITE. 22,[27][28][29][30][31][32] However, the AhR is betterknown for its ligation by a diverse group of xenobiotics, the most potent of which is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). 22 Agonist binding induces nuclear translocation of the AhR, which allows it to regulate expression of a variety of genes, including those of the cytochrome P450 family of drug-metabolizing enzymes.…”